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Original Research: Pulmonary Vascular Disease |

Regulatory T Cell Dysfunction in Idiopathic, Heritable and Connective Tissue-Associated Pulmonary Arterial Hypertension

Alice Huertas, MD, PhD; Carole Phan, MS; Jennifer Bordenave, MS; Ly Tu, PhD; Raphaël Thuillet, BS; Morane Le Hiress, PhD; Jérôme Avouac, MD, PhD; Yuichi Tamura, MD, PhD; Yannick Allanore, MD, PhD; Roland Jovan, MD; Olivier Sitbon, MD, PhD; Christophe Guignabert, PhD; Marc Humbert, MD, PhD
Author and Funding Information

FUNDING/SUPPORT: This research was supported by grants from the French National Institute for Health and Medical Research (INSERM, the French National Agency for Research: grant no. ANR 12 JSV1 0004 01), the Association des Sclérodermiques de France (ASF), and in part by the Département Hospitalo-Universitaire (DHU) Thorax Innovation (TORINO). M. L. H. was supported by the LabEx LERMIT (grant no. ANR-10-LABX-0033-LERMIT). Y. T. received a personal ERS/EU Marie Curie grant postdoctoral fellowship (RESPIRE2). C. P. is supported by the Fonds de Dotation “Recherche en Santé Respiratoire”—Fondation du Souffle.

CORRESPONDENCE TO: Alice Huertas, MD, PhD, INSERM UMR_S 999, Hôpital Marie Lannelongue, 133 Ave de la Résistance, 92350 Le Plessis-Robinson, France


Copyright 2016, American College of Chest Physicians. All Rights Reserved.


Chest. 2016;149(6):1482-1493. doi:10.1016/j.chest.2016.01.004
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Background  Pulmonary arterial hypertension (PAH) encompasses a group of conditions with distinct causes. Immunologic disorders are common features of all forms of PAH and contributes to both disease susceptibility and progression. Regulatory T lymphocytes (Treg) are dysfunctional in patients with idiopathic PAH (iPAH) in a leptin-dependent manner. However, it is not known whether these abnormalities are specific to iPAH. Hence, we hypothesized that (1) Treg dysfunction is also present in heritable (hPAH) and connective tissue disease-associated PAH (CTD-PAH); (2) defective leptin-dependent signaling is present in hPAH and CTD-PAH and could contribute to Treg dysfunction; (3) modulating the leptin axis in vivo could protect against Treg dysfunction; and (4) restoration of Treg activity could limit or reverse experimental chronic hypoxia-induced pulmonary hypertension in vivo.

Methods  We analyzed 62 patients with PAH (30 with iPAH, 18 with hPAH, and 14 with CTD-PAH), 7 patients with CTD without PAH, and 20 healthy control subjects.

Results  Our results indicate that Treg are dysfunctional in all PAH forms tested, as well as in patients with CTD without PAH. Importantly, the leptin axis is crucial in Treg dysfunction in patients with iPAH and those with CTD (with or without PAH), whereas in patients with hPAH, Treg are altered in a leptin-independent manner. We found that leptin receptor-deficient rats, which develop less severe hypoxia-induced pulmonary hypertension, are protected against decreased Treg function after hypoxic exposure.

Conclusions  Taken together, our results suggest that Treg dysfunction is common to all forms of PAH and may contribute to the development and the progression of the disease.

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